This Competing Continuation Application focuses on the Vasoactive Intestinal Peptide (VIP) and related neuropeptides of the lung. These newly identified peptides are localized in nerve elements supplying key structures in the lung, and can influence all major pulmonary function, including airway and vascular tone and reactivity, bronchial secretion, and vascular permeability. Lung peptides may be important in the pathogenesis of certain pulmonary diseases, notably bronchial asthma, cystic fibrosis and pulmonary hypertension, and some have therapeutic potential as bronchodilators and anti-inflammatory agents. The 4 complementary projects in this proposal are built on a solid basis of preliminary data, and have these specific goals: 1) to document the effectiveness of VIP in protecting the lung against severe injury, test the hypothesis that it is a physiological modulator of lung injury and inflammation, and determine the mechanisms of this protective action; 2) to characterize the active degradation of VIP by airway enzymes (which probably explains why aerosolized VIP is less effective in asthmatics than it is in experimental animals or in vitro), and compare this degradation to that of helodermin, a closely related peptide that produces prolonged tracheobronchial relaxation, possibly due to its relative resistance to airway peptidases; 3) to define the molecular, biochemical and pharmacologic properties of the VIP receptor in the lung, with special reference to alveolar macrophages and small-cell carcinoma cell lines; and 4) to delineate the anatomic pathways, neuronal origins, and colocalization of neuropeptides in the lung, and explore some of their functional interactions. Experimental methods include: measurement of peptide content in tissues and plasma by specific radioimmunoassays; immunocytochemical localization of these peptides in the lung; physiological monitoring of their effects on respiratory and hemodynamic function in isolated lungs and in vivo; biochemical studies of peptidase actions; and purification, solubilization and pharmacologic characterization of the VIP receptor.